DESCRIPTION: (Applicant's Abstract) Drug abuse is a major public health problem contributing to infectious diseases including AIDS and hepatitis, and cancer, partly through increased disease susceptibility of drug users. Drug addiction is largely associated with profound and negative impacts on physical and mental health and also has devastating social and economic consequences. Drugs such as opioids can promote the high incidence of infectious disease and HIV seropositivity in drug users by functioning as cofactors to alter host immune function, incidence of infection, and eventual development of AIDS in this population. The exact mechanism of action by which opioids induce immunosuppression remains to be determined. We plan to determine the cellular and molecular mechanisms of morphine-mediated immunosuppression through the sympathetic nervous system. Understanding the cellular and molecular mechanisms involved in adrenergic signaling, will allow to predict how adrenergic stimulation will alter leukocyte activity in vivo against infectious diseases and cancer. A. To determine the cellular mechanisms of centrally mediated opioid immunoregulation. We will examine structural and functional changes in lymphoid and myeloid populations from various organs, and production of cytokines, to evaluate the cellular events of opioid-induced immunosuppression. B. To determine the molecular mechanisms of centrally mediated opioid immunoregulation. Using molecular techniques, we will determine the intracellular mechanisms in opioid-mediated immunoregulation. We will measure the effects of opioids on G-protein activation, early signal transduction pathways involving changes in the levels of second messengers and protein phosphorylation, as well as protooncogene expression and activation of nuclear promoters for gene expression.